Synthesis and antiinflammatory/analgesic activities of 11H-dibenzo[b, e,][1,4]dioxepinacetic acids.

A new class of tricyclic arylacetic acids was synthesized and evaluated as antiinflammatory/analgesic agents as well as inhibitors of prostaglandin synthetase. 11H-Dibenzo[b,e][1,4]dioxepin-2-, -3, -7, and -8-acetic and alpha-methylacetic acids and their derivatives were prepared by cyclization of diaryl ether precursors or by condensation of catechol and an aryl dihalide. The most potent compound in the carrageenan foot edema assay was alpha-methyl-11H-dibenzo[b,e][1,4]dioxepin-8-acetic acid (1 mg/kg = 43% inhibition). The most potent enzyme inhibitors were the 2-acetic acid and the alpha-methyl-7-acetic acid (IC50 = 0.1 microM). Some of these compounds were also found to be highly ulcerogenic.

Inhibition by prostaglandins of leukotriene B4 release from activated neutrophils.

Chemoattractant N-formylmethionylleucylphenylalanine (fMet-Leu-Phe) in the presence of cytochalasin B stimulates the release of leukotriene B4 (LTB4), superoxide (O2-), and N-acetylglucosaminidase from elicited rat peritoneal and human peripheral neutrophils [PMN (polymorphonuclear leukocytes)]. Prostaglandins E1 and E2 (PGE1 and PGE2) inhibit LTB4 release from PMN in a dose-related manner with an IC50 of 1 X 10(-8) M. This action is associated with increased levels of cyclic AMP. The inhibitory activity of a variety of PGs on LTB4 production by rat peritoneal PMN parallels their affinity for PGE receptors in other tissues. O2- release is also suppressed by low levels of PGE1 and PGE2 in a dose-related manner and this inhibition is enhanced by theophylline. In contrast, lysosomal enzyme release is only minimally affected by physiological levels of PGs. These data are consistent with an action of PGs at the level of the PG receptor on LTB4 and O2- release from the fMet-Leu-Phe-stimulated rat peritoneal PMN. In addition, the fMet-Leu-Phe-induced adherence of PMN to endothelial cells and inhibition of this phenomenon by PGs may now be explained by PG-mediated inhibition of LTB4 formation.

A new iron-containing superoxide dismutase from Escherichia coli.

Escherichia coli B, grown under aerobic conditions, contains at least three distinct superoxide dismutases, which can be visualized on polyacrylamide gel electropherograms of crude soluble extracts of the sonically disrupted cells. Of these, the slowest migrating and the fastest migrating, respectively, have previously been isolated and characterized as manganese-containing and iron-containing enzymes. The enzyme form with medium electrophoretic mobility has now been purified to homogeneity. Its molecular weight is approximately 37,000 and it contains 0.8 atoms of iron/molecule and only negligible amounts of manganese. Like other iron-containing superoxide dismutases and unlike the corresponding manganienzymes, it is inactivated by EDTA plus H2O2. Its specific activity is comparable to that of the other superoxide dismutases of E. coli. Two types of subunits could be distinguished upon electrophoresis in the presence of sodium dodecyl sulfate. One of these migrated identically with the subunit obtained from the manganisuperoxide dismutase, while the other similarly appeared identical with the subunit from the ferrisuperoxide dismutase. This newly isolated enzyme thus appears to be a hybrid of the other two forms. In support of this conclusion, we observed that ultrafiltration or storage of the new superoxide dismutase gave rise to the mangani- and ferrienzymes on disc gel electrophoresis or isoelectric focussing.